Various publications are referred to throughout this application. Full citations for these references may be found at the end of the specification immediately preceding the claims. The disclosures of these publications are hereby incorporated by reference in their entireties into the subject application to more fully describe the art to which the subject application pertains.
Implantable medical devices such as tunneled catheters play a major role in general medicine. Aside from pneumothorax and hemorrhage-like complications which are associated with their initial insertion, catheters are associated with the long-term risks of infection and thrombosis [e.g., Harter et al. 2002; Safdar and Maki 2003; Saint et al. 2000]. Colonization of microorganisms on the surfaces of such devices following implantation can produce serious and costly complications, including the need to remove and/or replace the implanted device and/or vigorous treatment of secondary infections. Within days of insertion, almost all central venous catheters (CVCs) are coated with a fibrin sheath, and within 30 days, most catheter-related thrombi arise. Aside from reducing the function of the catheter, these catheter-related thrombi can cause postphlebitic syndrome in 15%-30% cases and pulmonary embolism in 11% of the cases [Kuter 2004]. An association of CVC-related infection with CVC-related thrombosis has been suggested [Raad et al. 1994; Rooden et al. 2005]. To minimize the risk of infection, chlorhexidine-silver sulfadiazine-impregnated or minocycline-rifampin-impregnated catheters [Mermel 2000] and, to minimize thrombosis, anticoagulant-coated catheters are utilized in clinics [Carrasco et al. 2004; Long and Coulthard 2006].
The art describes treatment of medical devices with antimicrobial and anticoagulants alone or in combination to provide dual benefits [Hanna et al. 2006; U.S. Pat. Nos. 5,451,424, 5,688,516, 5,707,366, 6,261,271, 6,273,875 B1, 6,528,107 B2]. Attachment of fibrinolytic enzymes to provide an antithrombogenic surface for medical device applications is also described [U.S. Pat. Nos. 4,273,873, 4,378,435]. Bacteriostatic organic alcohols have been proposed as preservatives for use with catheters coated with tissue-plasminogen activator [U.S. 2006/0257390]. However, enzymes, such as fibrinolytics, can be inactivated by a number of agents, including antimicrobial agents [e.g., U.S. Pat. No. 4,483,922] such as chlorhexidine [Pellat et al. 1991]. Ethanol, for example, is known to inhibit activity induced by urokinase and streptokinase [Roszkowska-Jakimiec et al. 1988-1989]. Treatment with fibrinolytic agents in combination with antimicrobial agents and the compatibility of these two classes of agents, where one agent does not adversely affect the activity of the other, has not been defined despite the need for catheters having combined fibrinolytic and antimicrobial properties.